4-(6-(2-(2,4-difluorophenyl)-1.1-difluoro-2-hydroxy-3-(5-mercapto-1h-1,2,4-triazol-1-yl)propyl)pyridin-3-yl)oxy)benzonitrile and processes of preparation

Abstract

Provided herein is a process for the preparation of 4-(6-(2-(2,4-difluorophenyl)-1.1-difluoro-2-hydroxy-3-(5-mercapto-1H-1,2,4-triazol-1-yl)propyl)pyridin-3-yl)oxy)benzonitrile.

1 . A method of making a compound of Formula I 
       
         
           
           
               
               
           
         
       
       comprising the step of contacting a compound of Formula II 
       
         
           
           
               
               
           
         
         wherein X is Cl, Br or I; 
       
       with an alkanedithiol, a copper salt and a base. 
     
     
         2 . The method of  claim 1 , wherein the copper salt may be selected from the group including CuSO 4 , CuCl 2 , CuBr 2 , Cu(acac) 2 , Cu(OAc) 2 , Cu(OH) 2 , CuO, and mixtures thereof. 
     
     
         3 . The method of  claim 1 , wherein the base is selected from the group including a metal carbonate, a metal alkoxide, a metal phosphate, and a metal hydroxide. 
     
     
         4 . The method of  claim 1 , wherein the base is selected from the group including potassium carbonate, sodium carbonate, and cesium carbonate. 
     
     
         5 . The method of  claim 1  further comprising a solvent selected from the group including acetonitrile, N,N-dimethylacetamide, dimethylsulfoxide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, sulfolane, and mixtures thereof, and mixtures of any of these solvents with water. 
     
     
         6 . The method of  claim 1  wherein the contacting is carried out between about 25° C. and about 200° C. 
     
     
         7 . The method of  claim 1  wherein the contacting is carried out between about 50° C. and about 150° C. 
     
     
         8 . The method of  claim 1 , further comprising the step of contacting a compound of Formula III 
       
         
           
           
               
               
           
         
       
       with a halogenating agent and a free radical initiator compound to prepare the compound of Formula II, wherein X is a Cl, Br, or I. 
     
     
         9 . The method of  claim 8 , wherein the halogenating agent may be selected from the group including NBS, NCS, NIS, Br 2 , Cl 2 , I 2 , 1,3-dibromo-5,5-dimethylhydantoin, 1,3-dichloro-5,5-dimethylhydantoin, 1,3-diiodo-5,5-dimethylhydantoin, and NaBr/H 2 O 2 . 
     
     
         10 . The method of  claim 8 , wherein the free radical initiator compound may be selected from benzoyl peroxide or azobisisobutyronitrile (AIBN). 
     
     
         11 . The method of  claim 8  further comprising a solvent selected from the group including acetonitrile, N,N-dimethylformamide, N-methyl-2-pyrrolidone, toluene, and ethyl acetate. 
     
     
         12 . The method of  claim 8  wherein the contacting is carried out between about 25° C. and about 150° C. 
     
     
         13 . The method of  claim 8  wherein the contacting is carried out between about 50° C. and about 125° C. 
     
     
         14 . A compound consisting of: 
       
         
           
           
               
               
           
         
         wherein X=Cl, Br or I.